Distinct dual roles of p-Tyr42 RhoA GTPase in tau phosphorylation and ATP citrate lyase activation upon different A beta concentrations

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Both the accumulation of Amyloid-beta (A beta) in plaques and phosphorylation of Tau protein (p-Tau) in neurofibrillary tangles have been identified as two major symptomatic features of Alzheimer's disease (AD). Despite of critical role of A beta and p-Tau in AD progress, the interconnection of signalling pathways that A beta induces p-Tau remains elusive. Herein, we observed that a popular AD model mouse (APP/PS1) and A beta-injected mouse showed an increase in p-Tyr42 Rho in hippocampus of brain. Low concentrations of A beta (1 mu M) induced RhoA-mediated Ser422 phosphorylation of Tau protein (p-Ser422 Tau), but reduced the expression of ATP citrate lyase (ACL) in the HT22 hippocampal neuronal cell line. In contrast, high concentrations of A beta (10 mu M) along with high levels of superoxide production remarkably attenuated accumulation of p-Ser422 Tau, but augmented ACL expression and activated sterol regulatory element-binding protein 1 (SREBP1), leading to cellular senescence. Notably, a high concentration of A beta(10 mu M) induced nuclear localization of p-Tyr42 Rho, which positively regulated NAD kinase (NADK) expression by binding to the NADK promoter. Furthermore, severe AD patient brain showed high p-Tyr42 Rho levels. Collectively, our findings indicate that both high and low concentrations of A beta are detrimental to neurons via distinct two p-Tyr42 RhoA-mediated signalling pathways in Ser422 phosphorylation of Tau and ACL expression.
Publisher
ELSEVIER
Issue Date
2020-05
Language
English
Article Type
Article
Citation

REDOX BIOLOGY, v.32

ISSN
2213-2317
DOI
10.1016/j.redox.2020.101446
URI
http://hdl.handle.net/10203/275417
Appears in Collection
BS-Journal Papers(저널논문)
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